Regeneration in humans
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Regeneration in humans is the regrowth of lost tissues or organs in response to injury. This is in contrast to
wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...
, or partial regeneration, which involves closing up the injury site with some gradation of
scar A scar (or scar tissue) is an area of fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other organs, and tissues of the body. Thus, scarring is a na ...
tissue. Some tissues such as skin, the
vas deferens The vas deferens or ductus deferens is part of the male reproductive system of many vertebrates. The ducts transport sperm from the epididymis to the ejaculatory ducts in anticipation of ejaculation. The vas deferens is a partially coiled tube ...
, and large organs including the liver can regrow quite readily, while others have been thought to have little or no capacity for regeneration following an injury. Numerous tissues and organs have been induced to regenerate. Bladders have been 3D-printed in the lab since 1999. Skin tissue can be regenerated ''
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'' or ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
''. Other organs and body parts that have been procured to regenerate include: penis, fats, vagina, brain tissue, thymus, and a scaled down human heart. One goal of scientists is to induce full regeneration in more human organs. There are various techniques that can induce regeneration. By 2016, regeneration of tissue had been induced and operationalized by science. There are four main techniques: regeneration by instrument; regeneration by materials; regeneration by drugs and regeneration by ''in vitro'' 3D printing.


History of human tissue

In humans with non-injured tissues, the tissue naturally regenerates over time; by default, new available cells replace expended cells. For example, the body regenerates a full bone within ten years, while non-injured skin tissue is regenerated within two weeks. With injured tissue, the body usually has a different response. This emergency response usually involves building a degree of scar tissue over a time period longer than a regenerative response, as has been proven clinically and via observation. There are many more historical and nuanced understandings about regeneration processes. In full thickness wounds that are under 2mm, regeneration generally occurs before scarring. In 2008, in full thickness wounds over 3mm, it was found that a wound needed a material inserted in order to induce full tissue regeneration. Whereas 3rd degree burns heal slowly by scarring, in 2016 it was known that full thickness fractional photothermolysis holes heal without scarring. Up to 40% of full thickness skin can be removed without scarring in an area, in a fractional pattern via coring of tissue. Some human organs and tissues regenerate rather than simply scar, as a result of injury. These include the liver, fingertips, and endometrium. More information is now known regarding the passive replacement of tissues in the human body, as well as the mechanics of
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
s. Advances in research have enabled the induced regeneration of many more tissues and organs than previously thought possible. The aim for these techniques is to use these techniques in the near future for the purpose of regenerating any tissue type in the human body.


Regeneration techniques

By 2016, regeneration had been operationalised and induced by four main techniques: regeneration by instrument; regeneration by materials; regeneration by 3d printing; and regeneration by drugs. By 2016, regeneration by instrument, regeneration by materials and by regeneration drugs had been generally operationalised
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
(inside living tissues). Whilst by 2016, regeneration by 3d printing had been generally operationalised by
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
(inside the lab) in order to be built and prepare tissue for transplantation.


By instrument

A cut by a knife or a scalpel generally scars, though a piercing by a needle does not. In 1976, a 3 by 3cm scar on a non-diabetic was regenerated by insulin injections and the researchers, highlighting earlier research, argued that the insulin was regenerating the tissue. The anecdotal evidence also highlighted that a syringe was one of two variables that helped bring regeneration of the arm scar. The syringe was injected into the four quadrants three times a day for eighty-two days. After eighty-two days, after many consecutive injections, the scar was resolved and it was noted no scar was observable by the human eye. After seven months the area was checked again and it was once again noted that no scar could be seen. In 1997, it was proven that wounds created with an instrument that are under 2mm can heal scar free, but larger wounds that are larger than 2mm healed with a scar. In 2013, it was proven in pig tissue that full thickness micro columns of tissue, less than 0.5mm in diameter could be removed and that the replacement tissue, was regenerative tissue, not scar. The tissue was removed in a fractional pattern, with over 40% of a square area removed; and all of the fractional full thickness holes in the square area healed without scarring. In 2016 this fractional pattern technique was also proven in human tissue.


With materials

Generally, humans can regenerate injured tissues in vivo for limited distances of up to 2mm. The further the wound distance is from 2mm the more the wound regeneration will need inducement. By 2009, via the use of materials, a max induced regeneration could be achieved inside a 1 cm tissue rupture. Bridging the wound, the material allowed cells to cross the wound gap; the material then degraded. This technology was first used inside a broken urethra in 1996. In 2012, using materials, a full urethra was restored in vivo. Macrophage polarization is a strategy for skin regeneration. Macrophages are differentiated from circulating monocytes. Macrophages display a range of phenotypes varying from the M1, pro-inflammatory type to the M2, pro-regenerative type. Material hydrogels polarise macrophages into the key M2 regenerative phenotype in vitro. In 2017, hydrogels provided full regeneration of skin, with hair follicles, after partial excision of scars in pigs and after full thickness wound incisions in pigs.


By 3D printing

In 2009, the regeneration of hollow organs and tissues with a long diffusion distance, was a little more challenging. Therefore, to regenerate hollow organs and tissues with a long diffusion distance, the tissue had to be regenerated inside the lab, via the use of a 3D printer. Various tissues that have been regenerated by in vitro 3D printing include: * The first organ ever induced and made in the lab was the bladder, which was created in 1999. * By 2014, there had been various tissues regenerated by the 3D printer and these tissues included: muscle, vagina, penis and the thymus. * In 2014, a conceptual human lung was first bioengineered in the lab. In 2015, the lab robustly tested its technique and regenerated a pig lung. The pig lung was then successfully transplanted into a pig without the use of immunosuppressive drugs. * In 2015, researchers developed a proof of principle biolimb inside a laboratory; they also estimated that it would be at least a decade for any testing of limbs in humans. The limb demonstrated fully functioning skin, muscles, blood vessels and bones. * In April 2019, researchers 3d printed a human heart. The prototype heart was made by human stem cells but only to the size of a rabbit's heart. In 2019, the researchers hoped to one day place a scaled up version of the heart inside humans.


Gradations of complexity

With printing tissues, by 2012, there were four accepted standard levels of regenerative complexity that were acknowledged in various academic institutions: * Level one, ''flat tissue'' like skin was the simplest to recreate; * Level two was ''tubular structures'' such as blood vessels; * Level three was ''hollow non-tubular structures''; * Level four was ''solid organs'', which were by far the most complex to recreate due to the vascularity. In 2012, within 60 days it was possible, inside the lab, to grow tissue the size of half a postage stamp to the size of a football field. Most cell types could be grown and expanded outside of the body, with the exception of the liver, nerve and pancreas, as these tissue types need stem cell populations.


With drugs

Lipoatrophy Lipoatrophy is the term describing the localized loss of fat tissue. This may occur as a result of subcutaneous injections of insulin in the treatment of diabetes, from the use of human growth hormone or from subcutaneous injections of copaxone us ...
is the localised loss of fat in tissue. It is common in diabetics who use conventional insulin injection treatment. In 1949, a much more pure form of insulin was, instead of causing lipoatrophy, shown to regenerate the localised loss of fat after injections in to diabetics. In 1984, it was shown that different insulin injections have different regenerative responses with regards to creating skin fats in the same person. It was shown in the same body that conventional forms of insulin injections cause lipoatrophy and highly purified insulin injections cause
lipohypertrophy Lipohypertrophy is a lump under the skin caused by accumulation of extra fat at the site of many subcutaneous injections of insulin. It may be unsightly, mildly painful, and may change the timing or completeness of insulin action. It is a common, ...
. In 1976, the regenerative response was shown to work in a non-diabetic after a 3 x 3cm lipoatrophic arm scar was treated with pure monocomponent porcine soluble insulin. A syringe injected insulin under the skin equally in the four quadrants of the defect. To layer four units of insulin evenly into the base of the defect, each quadrant of the defect received one unit of insulin three times a day, for eighty-two days. After eighty-two days of consecutive injections the defect regenerated to normal tissue. In 2016, scientists could transform a skin cell into any other tissue type via the use of drugs. The technique was noted as safer than genetic reprogramming which, in 2016, was a concern medically. The technique, used a cocktail of chemicals and enabled efficient on site regeneration without any genetic programming. In 2016, it was hoped to one day use this drug to regenerate tissue at the site of tissue injury. In 2017, scientists could turn many cell types (such as brain and heart) into skin.


Naturally regenerating appendages and organs


Heart

Cardiomyocyte necrosis activates an inflammatory response that serves to clear the injured myocardium from dead cells, and stimulates repair, but may also extend injury. Research suggests that the cell types involved in the process play an important role. Namely monocyte-derived macrophages tend to induce inflammation while inhibiting cardiac regeneration, while tissue resident macrophages may help restoration of tissue structure and function.


Endometrium

The
endometrium The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional laye ...
after the process of breakdown via the
menstruation cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs a ...
, re-epithelializes swiftly and regenerates. Though tissues with a non-interrupted morphology, like non-injured soft tissue, completely regenerate consistently; the endometrium is the only human tissue that completely regenerates consistently after a disruption and interruption of the morphology.


Fingers

In May 1932, L. H. McKim published a report describing the regeneration of an adult digit-tip following amputation. A house surgeon in the
Montreal General Hospital The Montreal General Hospital (MGH) (french: Hôpital Général de Montréal) is a hospital in Montreal, Quebec, Canada established in the years 1818-1820. The hospital received its charter in 1823. It is currently part of the McGill University ...
underwent amputation of the
distal phalanx The phalanges (singular: ''phalanx'' ) are digital bones in the hands and feet of most vertebrates. In primates, the thumbs and big toes have two phalanges while the other digits have three phalanges. The phalanges are classed as long bones. ...
to stop the spread of an infection. In less than one month following surgery, x-ray analysis showed the regrowth of bone while macroscopic observation showed the regrowth of nail and skin. This is one of the earliest recorded examples of adult human digit-tip regeneration. Studies in the 1970s showed that children up to the age of 10 or so who lose fingertips in accidents can regrow the tip of the digit within a month provided their wounds are not sealed up with flaps of skin – the de facto treatment in such emergencies. They normally will not have a
fingerprint A fingerprint is an impression left by the friction ridges of a human finger. The recovery of partial fingerprints from a crime scene is an important method of forensic science. Moisture and grease on a finger result in fingerprints on surfac ...
, and if there is any piece of the finger nail left it will grow back as well, usually in a square shape rather than round. In August 2005, Lee Spievack, then in his early sixties, accidentally sliced off the tip of his right middle finger just above the first phalanx. His brother, Dr. Alan Spievack, was researching regeneration and provided him with powdered
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
, developed by Dr. Stephen Badylak of th
McGowan Institute
of
Regenerative Medicine Regenerative medicine deals with the "process of replacing, engineering or regenerating human or animal cells, tissues or organs to restore or establish normal function". This field holds the promise of engineering damaged tissues and organs by st ...
. Mr. Spievack covered the wound with the powder, and the tip of his finger re-grew in four weeks. The news was released in 2007.
Ben Goldacre Ben Michael Goldacre (born 20 May 1974) is a British physician, academic and science writer. He is the first Bennett Professor of Evidence-Based Medicine and director of the Bennett Institute for Applied Data Science at the University of Oxford ...
has described this as "the missing finger that never was", claiming that fingertips regrow and quoted
Simon Kay Simon Peter Jabir Kay is a British consultant plastic surgeon, born and educated in Guernsey, Channel Islands, based in Leeds. Kay carried out the UK's first hand transplant operation. Kay trained in plastic surgery in the UK in Wexham Park Hosp ...
, professor of hand surgery at the
University of Leeds , mottoeng = And knowledge will be increased , established = 1831 – Leeds School of Medicine1874 – Yorkshire College of Science1884 - Yorkshire College1887 – affiliated to the federal Victoria University1904 – University of Leeds , ...
, who from the picture provided by Goldacre described the case as seemingly "an ordinary fingertip injury with quite unremarkable healing" A similar story was reported by CNN. A woman named Deepa Kulkarni lost the tip of her little finger and was initially told by doctors that nothing could be done. Her personal research and consultation with several specialists including Badylak eventually resulted in her undergoing regenerative therapy and regaining her fingertip.


Kidney

Regenerative capacity of the
kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
has been recently explored. The basic functional and structural unit of the kidney is
nephron The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...
, which is mainly composed of four components: the glomerulus, tubules, the collecting duct and peritubular capillaries. The regenerative capacity of the mammalian kidney is limited compared to that of lower vertebrates. In the mammalian kidney, the regeneration of the tubular component following an acute injury is well known. Recently regeneration of the
glomerulus ''Glomerulus'' () is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn". ''Glomerulus'' may refer to: * the filter ...
has also been documented. Following an acute injury, the proximal tubule is damaged more, and the injured epithelial cells slough off the basement membrane of the nephron. The surviving epithelial cells, however, undergo migration, dedifferentiation, proliferation, and redifferentiation to replenish the epithelial lining of the proximal tubule after injury. Recently, the presence and participation of kidney stem cells in the tubular regeneration has been shown. However, the concept of kidney stem cells is currently emerging. In addition to the surviving tubular epithelial cells and kidney stem cells, the bone marrow stem cells have also been shown to participate in regeneration of the proximal tubule, however, the mechanisms remain controversial. Studies examining the capacity of bone marrow stem cells to differentiate into renal cells are emerging. Like other organs, the kidney is also known to regenerate completely in lower vertebrates such as fish. Some of the known fish that show remarkable capacity of kidney regeneration are goldfish, skates, rays, and sharks. In these fish, the entire nephron regenerates following injury or partial removal of the kidney.


Liver

The human
liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
is particularly known for its ability to regenerate, and is capable of doing so from only one quarter of its tissue, due chiefly to the
unipotency Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta. According to Latin terms, Pluripotentia means the ability for many thin ...
of
hepatocyte A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, ...
s. Resection of liver can induce the proliferation of the remaining hepatocytes until the lost mass is restored, where the intensity of the liver's response is directly proportional to the mass resected. For almost 80 years surgical resection of the liver in rodents has been a very useful model to the study of cell proliferation.


Toes

Toes damaged by
gangrene Gangrene is a type of tissue death caused by a lack of blood supply. Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness. The feet and hands are most commonly affected. If the ga ...
and burns in older people can also regrow with the nail and toe print returning after medical treatment for gangrene.


Vas deferens

The
vas deferens The vas deferens or ductus deferens is part of the male reproductive system of many vertebrates. The ducts transport sperm from the epididymis to the ejaculatory ducts in anticipation of ejaculation. The vas deferens is a partially coiled tube ...
can grow back together after a
vasectomy Vasectomy, or vasoligation, is an elective surgical procedure for male sterilization or permanent contraception. During the procedure, the male vasa deferentia are cut and tied or sealed so as to prevent sperm from entering into the urethra and ...
–thus resulting in vasectomy failure. This occurs due to the fact that the
epithelium Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...
of the vas deferens, similar to the epithelium of some other human body parts, is capable of regenerating and creating a new tube in the event that the vas deferens is damaged and/or severed. Even when as much as five
centimeters 330px, Different lengths as in respect to the Electromagnetic spectrum, measured by the Metre and its deriveds scales. The Microwave are in-between 1 meter to 1 millimeter. A centimetre (international spelling) or centimeter (American spellin ...
, or two
inches Measuring tape with inches The inch (symbol: in or ″) is a unit of length in the British imperial and the United States customary systems of measurement. It is equal to yard or of a foot. Derived from the Roman uncia ("twelfth"), ...
, of the vas deferens is removed, the vas deferens can still grow back together and become reattached–thus allowing
sperm Sperm is the male reproductive cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm with a tail known as a flagellum, whi ...
to once again pass and flow through the vas deferens, restoring one's
fertility Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Fertili ...
.


Induced regeneration

There are several human tissues that have been successfully or partially induced to regenerate. Many fall under the topic of
regenerative medicine Regenerative medicine deals with the "process of replacing, engineering or regenerating human or animal cells, tissues or organs to restore or establish normal function". This field holds the promise of engineering damaged tissues and organs by st ...
, which includes the methods and research conducted with the aim of regenerating the organs and tissues of humans as a result of injury. The major strategies of regenerative medicine include dedifferentiating injury site cells, transplanting stem cells, implanting lab-grown tissues and organs, and implanting bioartificial tissues.


Bladder

In 1999, the bladder was the first regenerated organ to be given to seven patients; as of 2014, these regenerated bladders are still functioning inside the beneficiaries.


Fat

In 1949, purified insulin was shown to regenerate fat in diabetics with
lipoatrophy Lipoatrophy is the term describing the localized loss of fat tissue. This may occur as a result of subcutaneous injections of insulin in the treatment of diabetes, from the use of human growth hormone or from subcutaneous injections of copaxone us ...
. In 1976, after 82 days of consecutive injections into a scar, purified insulin was shown to safely regenerate fat and completely regenerate skin in a non-diabetic. During a high-fat diet, and during hair follicle growth, mature adipocytes (fats) are naturally formed in multiple tissues. Fat tissue has been implicated in the inducement of tissue regeneration. Myofibroblasts are the fibroblast responsible for
scar A scar (or scar tissue) is an area of fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other organs, and tissues of the body. Thus, scarring is a na ...
and in 2017 it was found that the regeneration of fat transformed myofibroblasts into adipocytes instead of scar tissue. Scientists also identified
bone morphogenetic protein Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens. Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of piv ...
(BMP) signalling as important for myofibroblasts transforming into adipocytes for the purpose of skin and fat regeneration.


Heart

Cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
s are the leading cause of death worldwide, and have increased proportionally from 25.8% of global deaths in 1990, to 31.5% of deaths in 2013. This is true in all areas of the world except Africa. In addition, during a typical
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
or heart attack, an estimated one billion cardiac cells are lost. The scarring that results is then responsible for greatly increasing the risk of life-threatening abnormal heart rhythms or
arrhythmias Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
. Therefore, the ability to naturally regenerate the heart would have an enormous impact on modern healthcare. However, while several animals can regenerate heart damage (e.g. the
axolotl The axolotl (; from nci, āxōlōtl ), ''Ambystoma mexicanum'', is a paedomorphic salamander closely related to the tiger salamander. Axolotls are unusual among amphibians in that they reach adulthood without undergoing metamorphosis. Instea ...
), mammalian
cardiomyocytes Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...
(heart muscle cells) cannot proliferate (multiply) and heart damage causes scarring and
fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
. Despite the earlier belief that human cardiomyocytes are not generated later in life, a recent study has found that this is not the case. This study took advantage of the nuclear bomb testing during the
Cold War The Cold War is a term commonly used to refer to a period of geopolitical tension between the United States and the Soviet Union and their respective allies, the Western Bloc and the Eastern Bloc. The term '' cold war'' is used because the ...
, which introduced carbon-14 into the atmosphere and therefore into the cells of nearby inhabitants. They extracted DNA from the myocardium of these research subjects and found that cardiomyocytes do in fact renew at a slowing rate of 1% per year from the age of 25, to 0.45% per year at the age of 75. This amounts to less than half of the original cardiomyocytes being replaced during the average lifespan. However, serious doubts have been placed on the validity of this research, including the appropriateness of the samples as representative of normally aging hearts. Further research has been conducted that supports the potential for human cardiac regeneration. Inhibition of p38 MAP kinase was found to induce mitosis in adult mammalian cardiomyocytes, while treatment with FGF1 and
p38 MAP kinase p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell different ...
inhibitors was found to regenerate the heart, reduce scarring, and improve cardiac function in rats with cardiac injury. One of the most promising sources of heart regeneration is the use of stem cells. It was demonstrated in mice that there is a resident population of stem cells or cardiac progenitors in the adult heart – this population of stem cells was shown to be reprogrammed to differentiate into cardiomyocytes that replaced those lost during a heart tissue death. In humans specifically, a "cardiac mesenchymal feeder layer" was found in the myocardium that renewed the cells with progenitors that differentiated into mature cardiac cells. What these studies show is that the human heart contains stem cells that could potentially be induced into regenerating the heart when needed, rather than just being used to replace expended cells. Loss of the myocardium due to disease often leads to heart failure; therefore, it would be useful to be able to take cells from elsewhere in the heart to replenish those lost. This was achieved in 2010 when mature cardiac
fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...
were reprogrammed directly into cardiomyocyte-like cells. This was done using three
transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...
:
GATA4 Transcription factor GATA-4 is a protein that in humans is encoded by the ''GATA4'' gene. Function This gene encodes a member of the GATA family of zinc finger transcription factors. Members of this family recognize the GATA motif which is pr ...
,
Mef2c Myocyte-specific enhancer factor 2C also known as MADS box transcription enhancer factor 2, polypeptide C is a protein that in humans is encoded by the ''MEF2C'' gene. MEF2C is a transcription factor in the Mef2 family. Genomics The gene is l ...
, and
Tbx5 T-box transcription factor TBX5, (T-box protein 5) is a protein that in humans is encoded by the ''TBX5'' gene. This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes ...
. Cardiac fibroblasts make up more than half of all heart cells and are usually not able to conduct contractions (are not cardiogenic), but those reprogrammed were able to contract spontaneously. The significance is that fibroblasts from the damaged heart or from elsewhere, may be a source of functional cardiomyocytes for regeneration. Simply injecting functioning cardiac cells into a damaged heart is only partially effective. In order to achieve more reliable results, structures composed of the cells need to be produced and then transplanted. Masumoto and his team designed a method of producing sheets of cardiomyocytes and vascular cells from human iPSCs. These sheets were then transplanted onto infarcted hearts of rats, leading to significantly improved cardiac function. These sheets were still found to be present four weeks later. Research has also been conducted into the engineering of heart valves. Tissue-engineered heart valves derived from human cells have been created in vitro and transplanted into a non-human primate model. These showed a promising amount of cellular repopulation even after eight weeks, and succeeded in outperforming currently-used non-biological valves. In 2021, researchers demonstrated a switchable iPSCs-
reprogramming In biology, reprogramming refers to erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development or in cell culture. Such control is also often associated with alternative covalent modifications of histones. ...
-based approach for regeneration of damaged heart without tumor-formation in mice. In April 2019, researchers
3d printed 3D printing or additive manufacturing is the construction of a three-dimensional object from a CAD model or a digital 3D model. It can be done in a variety of processes in which material is deposited, joined or solidified under computer co ...
a prototype human heart the size of a rabbit's heart.


Lung

Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...
(COPD) is one of the most widespread health threats today. It affects 329 million people worldwide, which makes up nearly 5% of the global population. Having killed over 3 million people in 2012, COPD was the third greatest cause of death. Worse still, due to increasing smoking rates and the aging populations in many countries, the number of deaths as a result of COPD and other chronic
lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...
diseases is predicted to continue increasing. Therefore, developments in the lung's capacity for regeneration is in high demand. It has been shown that bone marrow-derived cells could be the source of progenitor cells of multiple cell lineages, and a 2004 study suggested that one of these cell types was involved in lung regeneration. Therefore, a potential source of cells for lung regeneration has been found; however, due to advances in inducing stem cells and directing their differentiation, major progress in lung regeneration has consistently featured the use of patient-derived iPSCs and bioscaffolds. The
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
is the key to generating entire organs in vitro. It was found that by carefully removing the cells of an entire lung, a "footprint" is left behind that can guide cellular adhesion and differentiation if a population of lung epithelial cells and
chondrocytes Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteog ...
are added. This has serious applications in regenerative medicine, particularly as a 2012 study successfully purified a population of lung progenitor cells that were derived from embryonic stem cells. These can then be used to re-cellularise a three-dimensional lung tissue scaffold. Indeed, in 2008, there was a successful clinical transplantation of a tissue-engineered
trachea The trachea, also known as the windpipe, is a Cartilage, cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air, and so is present in almost all air-breathing animals with lungs. The trachea extends ...
in a 30-year-old woman with end-stage
bronchomalacia Bronchomalacia is a term for weak cartilage in the walls of the bronchial tubes, often occurring in children under a day. Bronchomalacia means 'floppiness' of some part of the bronchi. Patients present with noisy breathing and/or wheezing. There is ...
. An ECM scaffold was created by removing the cells and MHC antigens from a human donated trachea, which was then colonised by epithelial cells and mesenchymal stem cell-derived chondrocytes cultured from cells of the recipient. The graft replaced her left main bronchus, immediately providing a functional airway, and retained its normal appearance and mechanical function after four months. Because the graft was generated from cells cultured from the recipient, no anti-donor antibodies or
immunosuppressive drug Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified into ...
s were needed—a huge step towards personalised lung regeneration. A 2010 investigation took this one step further by using the ECM scaffold to produce entire lungs in vitro to be transplanted into living rats. These successfully enabled
gas exchange Gas exchange is the physical process by which gases move passively by Diffusion#Diffusion vs. bulk flow, diffusion across a surface. For example, this surface might be the air/water interface of a water body, the surface of a gas bubble in a liqui ...
but for short time intervals only. Nevertheless, this was a huge leap towards whole lung regeneration and transplants for humans, which has already taken another step forward with the lung regeneration of a non-human primate.
Cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...
is another disease of the lungs, which is highly fatal and genetically linked to a mutation in the CFTR gene. Through growing patient-specific lung epithelium in vitro, lung tissue expressing the cystic fibrosis phenotype has been achieved. This is so that modelling and drug testing of the disease pathology can be carried out with the hope of regenerative medical applications.


Penis

Penises have been successfully regenerated in the lab. Penises are harder to regenerate than the skin, bladder and vagina due to their structural complexity.


Spinal nerves

A goal of
spinal cord injury research Spinal cord injury research seeks new ways to cure or treat spinal cord injury in order to lessen the debilitating effects of the injury in the short or long term. There is no cure for SCI, and current treatments are mostly focused on spinal cord ...
is to promote
neuroregeneration Neuroregeneration refers to the regrowth or repair of nervous tissues, cells or cell products. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system ...
, reconnection of damaged neural circuits. The nerves in the spine are a tissue that requires a stem cell population to regenerate. In 2012, a Polish fireman
Darek Fidyka Dariusz "Darek" Fidyka (born ) is a Polish firefighter and recovering paraplegic who became the first person in history to verifiably recover sensory and motor function after the complete severing of his spinal cord. Having been paralysed fro ...
, with
paraplegia Paraplegia, or paraparesis, is an impairment in motor or sensory function of the lower extremities. The word comes from Ionic Greek () "half-stricken". It is usually caused by spinal cord injury or a congenital condition that affects the neural ...
of the spinal cord, underwent a procedure, which involved extracting
olfactory ensheathing cell Olfactory ensheathing cells (OECs), also known as olfactory ensheathing glia or olfactory ensheathing glial cells, are a type of macroglia (radial glia) found in the nervous system. They are also known as olfactory Schwann cells, because they e ...
s (OECs) from Fidyka's
olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a grey matter, neural structure of the vertebrate forebrain involved in olfaction, the sense of odor, smell. It sends olfactory information to be further processed in the amygdala, the orbitof ...
s, and injecting these stem cells, in vivo, into the site of the previous injury. Fidyka eventually gained feeling, movement and sensation in his limbs, especially on the side where the stem cells were injected; he also reported gaining sexual function. Fidyka can now drive and can now walk some distance aided by a frame. He is believed to be the first person in the world to recover sensory function from a complete severing of the spinal nerves.


Thymus

The thymus gland is one of the first organs to degenerate in normal healthy individuals. Researchers from the
University of Edinburgh The University of Edinburgh ( sco, University o Edinburgh, gd, Oilthigh Dhùn Èideann; abbreviated as ''Edin.'' in post-nominals) is a public research university based in Edinburgh, Scotland. Granted a royal charter by King James VI in 15 ...
have succeeded in regenerating a living organ that closely resembles a juvenile
thymus The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...
in terms of structure and gene expression profile.


Vagina

Between the years 2005 and 2008, four women with
vaginal hypoplasia Vaginal hypoplasia is the underdevelopment or incomplete development of the vagina. It is a birth defect or congenital abnormality of the female genitourinary system. Signs and symptoms Vaginal hypoplasia can vary in severity from being smaller t ...
due to
Müllerian agenesis Müllerian agenesis, also known as Müllerian aplasia, vaginal agenesis, or Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome), is a congenital malformation characterized by a failure of the Müllerian ducts to develop, resulting in a missi ...
were given regenerated vaginas. Up to eight years after the transplants, all organs have normal function and structure.


See also

*
Tissue engineering Tissue engineering is a biomedical engineering discipline that uses a combination of Cell (biology), cells, engineering, Materials science, materials methods, and suitable biochemistry, biochemical and physicochemical factors to restore, maintai ...


References


Further reading

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External links


UCI Limb Regeneration Lab
{{DEFAULTSORT:Regeneration (Biology) Vertebrate developmental biology Human biology Senescence